1. Field of the Invention
The present invention relates to a piperidine derivative and a process for preparing the same. More particularly, the present invention relates to a piperidine derivative useful as an intermediate for pharmaceuticals such as paroxetine and the like which are useful, for example, as an antidepressant.
2. Discussion of the Related Art
In general, paroxetine useful as an antidepressant is prepared by the processes described, for example, in Japanese Unexamined Patent Publication No. 7-138228 and Japanese Examined Patent Publication No. 59-46216.
However, these processes have the drawback that, upon deprotection of N-methyl group, complicated procedures such as hydrolysis after the transformation of N-methyl group to carbamate group are required.
In addition, there is disclosed a process for preparing paroxetine using an amidomalonic acid ester derivative as a starting material in, for example, Japanese Unexamined Patent Publication No. 7-138228. However, the amidomalonic acid ester derivative is not in general commercially available. Therefore, there necessitates troublesome procedures such that the amidomalonic acid ester derivative should be previously prepared before using.
An object of the present invention is to provide a compound useful as an intermediate for preparing paroxetine and a process for simply and industrially preparing the compound.
These and other objects of the present invention will be apparent from the following description.
Specifically, the present invention is concerned with the following:
(1) A piperidine derivative represented by the general formula (I): 
xe2x80x83wherein R1 is hydrogen atom, benzyloxycarbonyl group or tert-butoxycarbonyl group; R2 is hydroxymethyl group, an alkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl group which may have methyl group at the 4-position, (3,4-methylenedioxyphenyl)oxymethyl group, carboxyl group or xe2x80x94CO2R7 group in which R7 is an alkyl group having 1 to 5 carbon atoms, and Z is methylene group or carbonyl group, with proviso that,
(A) when R1 is benzyloxycarbonyl group or tert-butoxycarbonyl group, then R2 is hydroxymethyl group, an alkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl group which may have methyl group at the 4-position or (3,4-methylenedioxyphenyl)oxymethyl group, and Z is methylene group; or
(B) when R1 is hydrogen atom and Z is carbonyl group, then R2 is carboxyl group or xe2x80x94CO2R7 group (R7 is as defined above); or
(C) when R1 is hydrogen atom and Z is methylene group, then R2 is hydroxymethyl group;
(2) The piperidine derivative described in the above item (1), wherein the piperidine derivative is at least one member selected from (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)-oxymethyl]piperidine, (3SR,4RS)-trans-1-benzyloxy-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one, and (4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one;
(3) The piperidine derivative described in the above item (1), wherein R1 is tert-butoxycarbonyl group or benzyloxycarbonyl group, R2 is a group represented by the formula: 
xe2x80x83and Z is methylene group in the general formula (I);
(4) A method for preparing a piperidine derivative represented by the general formula (VII): 
wherein R3 is benzyl group or tert-butyl group, comprising the steps of:
reacting (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented by the formula (II): 
with a protecting reagent represented by the general formula (III): 
wherein R3 is as defined above; and Y is a chlorine atom or tert-butoxycarbonyloxy group, with proviso that
(A) when R3 is benzyl group, then Y is a chlorine atom,
(B) when R3 is tert-butyl group, then Y is tert-butoxycarbonyloxy group,
to give a carbamate compound represented by the general formula (IV): 
wherein R3 is as defined above;
reacting the carbamate compound with a sulfonic acid chloride represented by the general formula (V): 
wherein R4 is an alkyl group having 1 to 2 carbon atoms or a phenyl group which may have methyl group at the 4-position, to give a sulfonic acid ester represented by the general formula (VI): 
wherein R3 and R4 are as defined above;
reacting the sulfonic acid ester with 3,4-methylenedioxyphenol under basic conditions;
(5) A method for preparing (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented by the formula (II): 
xe2x80x83comprising the steps of:
optically resolving (4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one, to give (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one represented by the formula (VIII): 
and reducing the (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidine with a metal hydride compound;
(6) A method for preparing (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented by the formula (II): 
comprising the step of optically resolving (3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine;
(7) A method for preparing (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented by the formula (II): 
comprising the steps of:
transforming (xc2x1)-cis,trans-4-(4-fluorophenyl)-5-alkyloxycarbonylpiperidin-2-one represented by the general formula (IX): 
wherein R5 is an alkyl group having 1 to 4 carbon atoms; in the presence of a base, to give (4RS,5SR)-trans-4-(4-fluorophenyl)-5-alkyloxycarbonylpiperidin-2-one;
reducing the (4RS,5SR)-trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidin-2-one with a metal hydride compound, to give (3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine; and
optically resolving the (3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine;
(8) A method for preparing (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine comprising the step of catalytically reducing (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine, to deprotect the benzyloxycarbonyl group;
(9) A method for preparing a hydrochloride of (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine comprising the steps of:
catalytically reducing (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine, to deprotect the benzyloxycarbonyl group, to give (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine; and
treating the (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine with hydrogen chloride;
(10) The method described in the above item (9), wherein the (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine is treated with hydrogen chloride in isopropanol;
(11) A method for preparing a hydrochloride of (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine comprising the step of treating (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine with hydrogen chloride;
(12) The method described in the above item (11), wherein the (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine is treated with hydrogen chloride in isopropanol;
(13) A method for preparing a hydrochloride of (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine containing isopropanol, comprising the step of treating the isopropanol solution of a hydrochloride of (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine prepared by a method described in the above item (10) or item (12) with active carbon, to remove impurities; and
(14) A method for preparing an anhydrous hydrochloride of (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine having an isopropanol content of 0.1 to 5% by weight, comprising the steps of:
allowing precipitation of crystals of a hydrochloride of (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine from the isopropanol solution of the hydrochloride of (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine prepared by a method described in the above item (10), item (12), or item (13); and
drying the crystals under a reduced pressure at a temperature of from 80xc2x0 to 110xc2x0 C.
As described above, the piperidine derivative of the present invention is a compound represented by the general formula (I): 
wherein R1 is hydrogen atom, benzyloxycarbonyl group or tert-butoxycarbonyl group; R2 is hydroxymethyl group, an alkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl group which may have methyl group at the 4-position, (3,4-methylenedioxyphenyl)oxymethyl group, carboxyl group or xe2x80x94CO2R7 group in which R7 is an alkyl group having 1 to 5 carbon atoms, and Z is methylene group or carbonyl group, with proviso that,
(A) when R1 is benzyloxycarbonyl group or tert-butoxycarbonyl group, then R2 is hydroxymethyl group, an alkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl group which may have methyl group at the 4-position or (3,4-methylenedioxyphenyl)oxymethyl group, and Z is methylene group;
(B) when R1 is hydrogen atom and Z is carbonyl group, then R2 is carboxyl group or xe2x80x94CO2R7 group (R7 is as defined above); and
(C) when R1 is hydrogen atom and Z is methylene group, then R2 is hydroxymethyl group.
In the general formula (I), R1 is hydrogen atom, benzyloxycarbonyl group or tert-butoxycarbonyl group. R2 is hydroxymethyl group, an alkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl group which may have methyl group at the 4-position, (3,4-methylenedioxyphenyl)oxymethyl group, carboxyl group or xe2x80x94CO2R7 group in which R7 is as defined above. Z is methylene group or carbonyl group.
(A) When R1 is benzyloxycarbonyl group or tert-butoxycarbonyl group, then R2 is hydroxymethyl group, an alkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl group which may have methyl group at the 4-position or (3,4-methylenedioxyphenyl)oxymethyl group, and Z is methylene group.
(B) When R1 is hydrogen atom and Z is carbonyl group, then R2 is carboxyl group or xe2x80x94CO2R7 group (R7 is as defined above).
(C) When R1 is hydrogen atom and Z is methylene group, R2 is hydroxymethyl group.
In the general formula (I),
(A) when R1 is benzyloxycarbonyl group or tert-butoxycarbonyl group, then R2 is hydroxymethyl group, an alkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl group which may have methyl group at the 4-position or (3,4-methylenedioxyphenyl)oxymethyl group, and Z is methylene group; and
(C) when R1 is hydrogen atom and Z is methylene group,
then R2 is hydroxymethyl group,
there can be cited as the specific examples of the piperidine derivative represented by the general formula (I), for instance, (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(p-toluylsulfonyloxymethyl)piperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine, (3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-1-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, and (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.
In the general formula (I), when R1 is hydrogen atom and Z is carbonyl group, and R2 is carboxyl group or xe2x80x94CO2R7 group, in which R7 is as defined above, examples of the piperidine derivatives represented by the general formula (I) include (xc2x1)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one, (xc2x1)-trans-4-(4-fluorophenyl)-5-ethoxycarbonylpiperidin-2-one, (xc2x1)-trans-4-(4-fluorophenyl)-5-propoxycarbonylpiperidin-2-one, (xc2x1)-trans-4-(4-fluorophenyl)-5-isopropoxycarbonylpiperidin-2-one, (xc2x1)-trans-4-(4-fluorophenyl)-5-butoxycarbonylpiperidin-2-one, (xc2x1)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one, (xc2x1)-cis-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one, (xc2x1)-cis-4-(4-fluorophenyl)-5-ethoxycarbonylpiperidin-2-one, (xc2x1)-cis-4-(4-fluorophenyl)-5-propoxycarbonylpiperidin-2-one, (xc2x1)-cis-4-(4-fluorophenyl)-5-isopropoxycarbonylpiperidin-2-one, (xc2x1)-cis-4-(4-fluorophenyl)-5-butoxycarbonylpiperidin-2-one, and (xc2x1)-cis-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.
Among the above piperidine derivatives, there can be particularly preferably used in the present invention, at least one member selected from (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine, (3S,4R)-trans-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one, and (4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.
As the starting material for the piperidine derivative represented by the general formula (I), 4-fluorobenzaldehyde can be used.
The above 4-fluorobenzaldehyde is reacted with an acetic acid ester represented by the general formula:
CH3COOR5,
wherein R5 is an alkyl group having 1 to 4 carbon atoms to give a 4-fluorocinnamic acid ester. A cyanoacetic acid ester represented by the general formula:
NCxe2x80x94CH2xe2x80x94CO2xe2x80x94R6,
wherein R6 is an alkyl group having 1 to 4 carbon atoms is reacted with the resulting 4-fluorocinnamic acid ester to give a glutaric acid ester derivative represented by the general formula (X): 
wherein R5 and R6 are as defined above. Then, the resulting glutaric acid ester derivative can be reduced to give (xc2x1)-cis,trans-4-(4-fluorophenyl)-5-alkyloxycarbonylpiperidin-2-one represented by the general formula (IX): 
wherein R5 is as defined above.
The reduction is preferably catalytic hydrogenation, and the reaction conditions are not limited to specified ones. When the catalytic hydrogenation is performed, for example, a conventional catalytic hydrogenation conditions can be employed where cyano group of the glutaric acid ester derivative represented by the general formula (X) is catalytically hydrogenated to aminomethyl group. In this case, as the catalyst, for example, Raney cobalt, Raney nickel, palladium-carbon, platinum-carbon and the like can be used. As a solvent, there can be cited, for instance, hydrocarbon solvents such as toluene, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran (THF), alcohol solvents such as methanol, and a mixture thereof. The reaction temperature can be usually within a range of room temperature to 150xc2x0 C., and the hydrogen pressure can be, for example, within a range of 0.5 to 150 kgf/cm2. Upon reaction, starting materials containing the compound represented by the general formula (X) can be introduced in the reaction vessel at a time, or the compound represented by the general formula (X) can be added to the reaction system under pressure.
The compound (xc2x1)-cis,trans-4-(4-fluorophenyl)-5-alkyloxycarbonylpiperidin-2-one represented by the general formula (IX) includes a cis-isomer and a trans-isomer as main components. In order to obtain the trans-isomer and the cis-isomer from the mixture separately thereof, there can be employed a usual method for the separation of compounds, such as utilizing the solubility difference in a solvent, and a conventional column separation for organic compounds. The cis-isomer can be converted into the trans-isomer in the presence of a base. Also, the cis-isomer can be converted into the trans-isomer in the form of an acid, for example, by alkaline hydrolysis.
When the above-mentioned isomerization of the (xc2x1)-cis, trans esters is carried out, for example, by using a sodium alkoxide as a catalyst to obtain crystals, the trans-isomer can be preferentially obtained in the form of an ester.
Also, when (xc2x1)-cis, trans-esters are heated to reflux using sodium hydroxide in an alcohol or in water, the cis-ester is presumably first transformed into the trans-ester and hydrolyzed to give a trans-acid.
The (xc2x1)-cis,trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidin-2-one represented by the general formula (IX) can be converted into an optically active trans-carboxylic acid or its ester by transforming the above compound into a trans-carboxylic acid ester in the same manner as the above and hydrolyzing its ester portion using, for example, an enzyme, or by transforming the above compound into a trans-carboxylic acid and asymmetrically esterifying its carboxylic acid portion using an enzyme.
Also, the above racemic trans-carboxylic acid can be resolved into an optically active trans-carboxylic acid by a usual method for preparing a diastereomer derivative, for example, by a method comprising preparing a salt of the above trans-carboxylic acid and an optically active amine, and separating the salt therefrom as crystals.
More specifically, the optical resolution of (xc2x1)-trans-carboxylic acid, that is, (4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one, can be carried out usually in a solvent in the presence of an optically active amine.
Representative examples of the optically active amines include compounds disclosed, for example, in Japanese Unexamined Patent Publication No. 6-116214. More particularly, there can be cited, for instance, R-(xc2x1)-N-(4-hydroxyphenylmethyl)phenylmethylamine, and the like.
It is desired that the amount of the optically active amine to be used is 0.5 to 1.2 moles, preferably 0.6 to 1.1 moles per 1 mole of (4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.
Examples of the solvents include alcohols such as methanol, ethanol, esters such as ethyl acetate, and the like. Those solvents can be used alone or in admixture thereof. If necessary, those solvents can be used in admixture with water.
The (4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one and the optically active amine can be dissolved in the solvent, mixed and allowed to stand or stirred to optically resolve the (4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.
At this stage, it is desired that the temperature of the mixture is usually xe2x88x9210xc2x0 to 120xc2x0 C., preferably 10xc2x0 to 90xc2x0 C.
After the completion of the optical resolution, the precipitated crystals of the salts are filtered and the resulting crystals are degraded under acidic or alkaline conditions.
When the resulting crystals of the salts are degraded under alkaline conditions, the crystals are treated with alkaline such as sodium hydroxide or the like in the presence of water, and optically active amine is extracted from its aqueous layer with an organic solvent. Thereafter, the alkaline aqueous solution is made acidic to give crystals of (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.
Also, when the resulting crystals of the salts are degraded under acidic conditions, the crystals are treated with acidic aqueous solution such as sulfuric acid, hydrochloric acid or the like to give an aimed crystalline (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one. The optically active amine can be recovered from the remaining acidic aqueous solution by neutralizing the acidic aqueous solution e.g. with sodium hydroxide and extracting with an organic solvent.
The resulting crystals can be filtered and dried for use in the next reduction reaction.
The (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one can be reduced to give (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented by the formula (II): 
Upon the reduction reaction, a metal hydride compound (reducing agent) such as diborane, borane complex, boron hydride compound generated from sodium boron hydride in situ, or aluminum hydride compound such as aluminum hydride, diisobutylaluminum hydride or lithium aluminum hydride can be used. It is desired that the amount of the metal hydride compound to be used is usually 6 to 12 equivalents as an active hydride per 1 equivalent of the (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one. There can be employed conventional reducing conditions where a carboxylic acid is reduced to a primary alcohol. That is, as a reaction solvent, there can be employed, for example, an ether solvent such as tetrahydrofuran (THF), and a mixed solvent of the ether solvent and a hydrocarbon solvent such as toluene. The reaction temperature can be, for example, within a range of ordinary temperature to 100xc2x0 C. Upon reaction, for example, when the aluminum hydride compound is used, the reaction is desirably carried out by adding dropwise the (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one thereto.
Alternatively, (4RS,5SR)-trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidin-2-one obtained by isomerizing (xc2x1)-cis,trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidin-2-one represented by the general formula (IX) in the presence of a base can be reduced with a metal hydride reducing agent to give (3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. Thereafter, the (3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine can be optically resolved with an optically active organic acid to give an optically active compound represented by the formula (II).
As the metal hydride reducing agent, there can be exemplified those used for reducing the (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.
As the optically active organic acid, there can be used, o-chlorotartranilic acid described in J. Org. Chem., 33, 3993 (1968), and the like.
As the conditions such as the amount of the optically active acid to be used, and kinds of the solvent used for resolution and the amount thereof, those used for the optical resolution of the (4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one can be employed. In addition, as a solvent, water or a mixture of water and acetone can be used.
From (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine thus obtained represented by the formula (II), the piperidine derivative represented by the general formula (I) of the present invention where Z represents methylene group can be obtained as follows:
First, a process for preparing the piperidine derivative represented by the general formula (I) wherein R1 is benzyloxycarbonyl group and Z is methylene group is explained.
The compound (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented by the formula (II) can be reacted with a protective reagent represented by the general formula (III): 
wherein R3 is benzyl group and Y is chlorine atom, to give a carbamate compound represented by the general formula (IV): 
wherein R3 is benzyl group.
The above reaction can be carried out, for example, by reacting (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine with the protective reagent represented by the general formula (III) in the presence of a base such as an aqueous sodium bicarbonate solution, but this process does not limit the scope of the present invention.
The carbamate compound represented by the general formula (IV) can be reacted with an organosulfonic acid chloride represented by the general formula (V): 
wherein R4 is an alkyl group having 1 to 2 carbon atoms or phenyl group which may have methyl group at the 4-position, for example, in the presence of an acid acceptor such as triethylamine, to give an organosulfonic acid ester represented by the general formula (VI): 
wherein R3 is benzyl group, and R4 is methyl group, ethyl group, phenyl group or 4-methylphenyl group.
More specifically, for example, the carbamate compound represented by the general formula (IV) can be reacted with methanesulfonyl chloride in the presence of the acid acceptor to give (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine represented by the general formula (I), wherein R1 is benzyloxycarbonyl group, R2 is methylsulfonyloxymethyl group, and Z is methylene group.
In addition, for example, the carbamate compound represented by the general formula (IV) can be reacted with ethanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride in the presence of the acid acceptor to give (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine or (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine represented by the general formula (VI), wherein R3 is benzyl group and R4 is methyl group, phenyl group or 4-methylphenyl group (toluyl group), respectively.
Further, the organosulfonic acid ester represented by the general formula (VI) can be reacted with 3,4-methylenedioxyphenol in the presence of a base to give (3S, 4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine represented by the general formula (VII): 
wherein R3 is benzyl group, which can also be represented by the general formula (I), wherein R1 is benzyloxycarbonyl group, R2 is 3,4-methylenedioxyphenyloxymethyl group, and Z is methylene group.
Next, a process for preparing the piperidine derivative represented by the general formula (I) wherein R1 is tert-butoxycarbonyl group and Z is methylene group is explained.
When (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented by the formula (II) is reacted with di-tert-butyl dicarbonate as a protecting reagent for aminoic nitrogen, it is preferable that 1 to 2 moles of di-tert-butyl dicarbonate is usually used per 1 mole of (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.
Upon the reaction, a solvent which is unreactive to the (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine and di-tert-butyl dicarbonate can be used.
Examples of the solvent include hydrocarbon solvents represented by toluene, ether solvents represented by tetrahydrofuran, ketone solvents represented by methyl isobutyl ketone, and ester solvents represented by ethyl acetate. Those solvents can be usually used alone or in admixture thereof.
The amount of the solvent to be used is not specified but preferably in the range such that the total amount of the (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine and di-tert-butyl dicarbonate is usually 20 to 100 parts by weight based upon 100 parts by weight of the solvent.
Upon the reaction, a catalyst can be used if necessary. As the catalyst, there can be cited, for example, organic basic catalysts such as tertiary amines such as triethylamine.
The reaction temperature is not limited to specified ones but can be usually within a range of around 0xc2x0 C. to a boiling point of the solvent.
The reaction atmosphere is not limited to specified ones, but the reaction can be usually carried out in an ambient atmosphere or in an inert gas such as nitrogen gas.
As a result of the reaction, there can be obtained the carbamate compound represented by the general formula (IV) wherein R3 is tert-butyl group.
Then, the resulting carbamate compound represented by the general formula (IV) is reacted with organosulfonic acid chloride represented by the general formula (V).
It is desired that the reaction of the carbamate compound represented by the general formula (IV) with the organosulfonic acid chloride represented by the general formula (V) is usually carried out under the condition such that 0.95 to 1.2 moles of the organosulfonic acid chloride represented by the general formula (V) is used per 1 mole of the starting material (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.
Upon the reaction of the carbamate compound represented by the general formula (IV) with the organosulfonic acid chloride represented by the general formula (V), the reaction conditions, more specifically, solvent, catalyst, reaction temperature and reaction atmosphere can be the same as those for the reaction of (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented by the formula (II) and di-tert-butyl dicarbonate.
In the present invention, after the completion of the reaction of (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented by the formula (II) and di-tert-butyl dicarbonate, the successive reaction can be achieved by adding the organosulfonic acid chloride represented by the general formula (V) and an acid acceptor to the reaction mixture if necessary after the removal of the azeotropic water from the reaction mixture.
Thus, there is obtained a carbamate compound represented by the general formula (VI), wherein R3 is benzyl group or tert-butyl group.
Then, the organosulfonic acid ester represented by the general formula (VI) is reacted with 3,4-methylenedioxyphenol in the presence of a base.
It is desired that the amount of 3,4-methylenedioxyphenol to be used is usually 1 to 3 moles or so per 1 mole of the organosulfonic acid ester represented by the general formula (VI).
As a reaction solvent to be used for reacting the organosulfonic acid ester represented by the general formula (VI) with 3,4-methylenedioxyphenol, there can be cited, for example, lower alcohol solvents having 1 to 4 carbon atoms, polar organic solvents such as amide solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide, and hydrocarbon solvents such as toluene. Those solvents can be usually used alone or in admixture thereof.
The amount of the solvent to be used is not limited to specified ones but is preferably such that the total amount of the organosulfonic acid ester represented by the general formula (VI) and 3,4-methylenedioxyphenol is usually 20 to 100 parts by weight, based upon 100 parts by weight of the solvent.
As the base, there can be cited, for example, sodium hydride, sodium methoxide, sodium amide, potassium tert-butoxide, sodium hydroxide and sodium carbonate.
It is preferable that the amount of the base to be used is usually 0.8 to 1 mole per 1 mole of 3,4-methylenedioxyphenol.
The reaction temperature can be usually within a range of ordinary temperature to the boiling point of the solvent. The reaction can be performed under pressure if necessary.
The reaction atmosphere is not limited to specified ones, but the reaction can be usually carried out in an ambient atmosphere or in an inert gas such as nitrogen gas.
The piperidine derivative (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine thus obtained, represented by the general formula (VII), wherein R3 is benzyl group, can be catalytically hydrogenolyzed to deprotect a protecting group, i.e. benzyloxycarbonyl group. The deprotection of the benzyloxycarbonyl group can be carried out, for example, as follows:
The (3S, 4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl )-3-[(3, 4-methylenedioxyphenyl)oxymethyl]-piperidine is dissolved in a solvent and the reaction can be carried out by stirring in hydrogen gas atmosphere in the presence of a catalyst.
As the catalyst, there can be cited, for instance, palladium-carbon, and the like. It is desired that the amount of the catalyst is usually 1 to 10 parts by weight or so based upon 100 parts by weight of the (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl )-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.
As the solvent, there can be cited, for instance, hydrocarbon solvents such as toluene, ether solvents such as tetrahydrofuran, alcohol solvents such as methanol, and a mixture thereof.
The reaction temperature can be usually within a range of ordinary temperature to 100xc2x0 C.
The pressure of hydrogen gas to be introduced in the solution is not limited to specified ones but can be usually ordinary atmospheric pressure to around 20 kgf/cm2. It is desired that the amount of hydrogen gas to be introduced in the solution is usually at least 1 mole per 1 mole of the (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine.
The reaction time is not limited to specified ones but can be a time until the completion of the reaction. The completion of the reaction can be monitored, for example, by chromatography and can be a point at which the (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine disappears.
Thus, (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine is obtained.
After (3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine is catalytically hydrogenolyzed to deprotect benzyloxycarbonyl group, hydrogen chloride can be added thereto to give (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine hydrochloride. When hydrogen chloride is reacted on the (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine in a nonaqueous anhydrous solvent, anhydrous (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine hydrochloride is obtained, which is useful as an antidepressant.
As a method for preparing anhydrous hydrochloride of the (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine from the (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine, there can be employed, for example, the following method.
The (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine is first dissolved in a nonaqueous solvent.
As the non-aqueous solvent, there can be cited, for instance, hydrocarbon solvents such as toluene, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran, halogenated solvents such as dichloromethane, alcohol solvents such as ethanol and isopropanol, and a mixture thereof.
Then, hydrogen chloride gas is introduced in the resulting solution. The use of dry hydrogen chloride gas is preferable from the viewpoint that the incorporation of moisture in the reaction system is avoided. In the present invention, a nonaqueous solvent containing hydrogen chloride in it can be added to the solution.
It is desired that the amount of hydrogen chloride to be introduced in the solution is usually at least 1 mole per 1 mole of the (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.
The reaction temperature can be usually within a range of ordinary temperature to the boiling point of the solvent.
The reaction time is not limited to specified ones but can be a time until the completion of the reaction. The completion of the reaction can be a point at which the weight of absorbed hydrogen chloride reaches a required amount.
Next, the deprotection of tert-butoxycarbonyl group of the (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine represented by the general formula (VII), wherein R3 is tert-butyl group can be carried out by reacting hydrogen chloride on (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine in isopropanol to give (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine hydrochloride. This reaction is a reaction for deprotecting tert-butoxycarbonyl group.
The amount of (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl )oxymethyl]-piperidine to be mixed with ispropanol is not limited to specified ones, but usually the amount is preferably 5 to 50 parts by weight based upon 100 parts by weight of the isopropanol.
It is desired that the amount of hydrogen chloride to react on (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine is usually 1 to 5 moles per 1 mole of (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.
In the present invention, for example, other organic solvent and organic acid may be conveniently added thereto in an amount so as not to impair the object of the present invention.
As the method for reacting hydrogen chloride thereon, there can be cited, for instance, a method of first dissolving hydrogen chloride in isopropanol, and adding the (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine thereto while stirring, a method of introducing hydrogen chloride gas into a solution obtained by dissolving the (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine in isopropanol, or a method of adding a solution obtained by dissolving hydrogen chloride gas in isopropanol to the above (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine while stirring, and the like.
The temperature when hydrogen chloride is reacted thereon varies depending upon the amount of hydrogen chloride used and is usually within a range of ordinary temperature to the boiling point of isopropanol when the amount of hydrogen chloride is within a range of 1 to 2 mole per 1 mole of the (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.
When the hydrogen chloride is reacted thereon, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine hydrochloride is formed, at the same time that the tert-butoxycarbonyl group is deprotected.
The (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine hydrochloride isopropanol solution thus obtained contains impurities in some cases. In this case, the isopropanol solution can be treated with activated carbon to remove the impurities.
Next, the isopropanol solution is gradually cooled to obtain crystals of (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine hydrochloride having good filtration properties.
Usually, isopropanol is incorporated in a content of 8 to 15% by weight in the thus obtained-crystals of (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine hydrochloride.
The crystals of the (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine hydrochloride are dried, for example, at 80xc2x0 to 110xc2x0 C. under reduced pressure to convert the crystals from those having the maximum endothermic peak at a temperature range of 98xc2x0 to 110xc2x0 C. to those having the maximum endothermic peak at a temperature range of 118xc2x0 to 132xc2x0 C. as measured by DSC (differential scanning calorimetry). The reason why the heating temperature is adjusted to not lower than 80xc2x0 C. is to rapidly dry isopropanol. The reason why the heating temperature is adjusted to not higher than 110xc2x0 C. is to avoid melting of the crystals.
The crystals thus converted are composed of anhydrous (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine hydrochloride having an isopropanol content of 0.1 to 5% by weight.
The anhydrous hydrochloride is a compound useful as an antidepressant.